Temporal trends in the incidence and outcomes of shock-refractory ventricular fibrillation out-of-hospital cardiac arrest

Aim We aimed to describe trends in the incidence and outcomes of refractory ventricular fibrillation (RVF) compared to non-refractory ventricular fibrillation (non-RVF) in out-of-hospital cardiac arrest (OHCA). Methods Between 2010 and 2019, we included all OHCA cases involving adults ≥ 16 years old with an initial shockable rhythm and who received an attempted resuscitation by Emergency Medical Services (EMS) or a bystander shock prior to EMS arrival in Victoria, Australia. Trends in incidence and survival outcomes over the study period were examined. Adjusted logistic regression analyses were conducted to examine factors associated with RVF, as well as the association of RVF on survival to hospital discharge. RVF refers to patients receiving three or more consecutive shocks without a return of spontaneous circulation (ROSC). Results Of the 57,749 OHCA attended by EMS, 7,267 met the inclusion criteria. Of these, 4,168 (57.4%) were non-RVF and 3,099 (42.6%) were RVF. The incidence of RVF decreased significantly from 7.7 per 100,000 population in 2010 to 5.6 per 100,000 population in 2019 (p-trend = 0.01). Survival to hospital discharge increased significantly for both the RVF and non-RVF groups (26% vs 41% in 2010 to 31% vs 53% in 2019, p-trend = 0.004 for RVF; and p-trend = 0.01 for non-RVF). Compared to non-RVF, RVF was associated with reduced odds of survival to hospital discharge (Odds Ratio = 0.503 [95% confidence interval 0.448 – 0.565]). Factors associated with a lower likelihood of RVF and improved survival to hospital discharge included being witnessed to arrest by EMS, receiving bystander defibrillation and bystander cardiopulmonary resuscitation (CPR). Conclusion The incidence of RVF is declining, and survival rates are improving. Early treatment of VF patients with bystander CPR and defibrillation is likely to reduce RVF incidence.


Introduction
Globally, out-of-hospital cardiac arrest (OHCA) affects 55 adults per 100,000 people, with a survival rate of 8.8%. 1,2Approximately onequarter of all EMS-treated OHCA events present with Ventricular Fibrillation (VF) or pulseless Ventricular Tachycardia (VT) as the initial cardiac rhythm, 1,3 and these patients are reported to have better survival outcomes, between 10% and 30%. 1 However, despite receiving multiple defibrillations, repeated doses of epinephrine and antiarrhythmic drugs, more than half of patients with VF/VT do not respond to conventional treatment and often do not survive. 4This condition is known as shock-refractory Ventricular Fibrillation (RVF).
Although the definition of RVF is still unclear, 5 it is often defined as patients with at least three consecutive defibrillation attempts without achieving (ROSC). 6,7Many studies exploring RVF included a combination of refractory and recurrent VF cases, where recurrent VF refers to the transient conversion of ventricular arrythmias followed by their rapid recurrence, usually between rhythm analysis cycles. 7Challenges in obtaining and analysing electrocardiogram records real-time make distinguishing between the two groups impractical. 7hile changes in the incidence of shockable rhythms over time have been reported in the literature, 8 changes in the incidence of RVF and non-RVF remain under investigated.To our knowledge, https://doi.org/10.1016/j.resplu.only one study, conducted in Japan, reported the long-term incidence and outcomes of RVF.The incidence of RVF was 0.5 per 100,000 population per year, and this remained unchanged over the study period. 8On the other hand, studies have reported a high survival to hospital discharge rate among RVF patients undergoing extracorporeal membrane oxygenation (ECMO) treatment. 9However, its implementation poses challenges due to feasibility and resource demands. 10Furthermore, it is unclear if patient outcomes are changing over time for RVF, or whether its occurrence is potentially modifiable through community or EMS care provision.As such, there is a need to examine temporal patterns in the incidence and outcome of RVF relative to non-refractory cases of VF/VT.
In this study, we sought to provide an epidemiological analysis of the temporal trends in the incidence of RVF and non-RVF OHCA in Victoria, Australia.In addition, we aimed to identify risk factors for the development of RVF, and examine the impact of RVF on survival to hospital discharge.

Study design
A retrospective cohort study was performed using data from the Victorian Ambulance Cardiac Arrest Registry (VACAR).We included all adults aged 16 years old with an initial shockable rhythm and who received an attempted resuscitation by emergency medical services (EMS) or a bystander shock prior to EMS arrival between January 2010 and December 2019.We excluded cases of traumatic aetiology and cases where the number of administered shocks was not documented.Ethical approval for this study was obtained from the Monash University Human Research and Ethics Committee (Project ID: 36838).

Setting
The State of Victoria, Australia, has a population of more than 6.6 million people, distributed across an area of 227,500 square kilometres.The EMS is operated by Ambulance Victoria, a single statewide EMS system.Annually, Ambulance Victoria attends to more than 7,000 OHCA cases. 11The EMS has three levels of response to suspected cardiac arrest events, including Basic Life Support first responders, Advanced Life Support paramedics and intensive care paramedics.Local treatment guidelines follow the recommendations of the Australian and New Zealand Committee on Resuscitation (https://www.anzcor.org).First responders include firefighters and community volunteers who are trained in basic life support and Automated External Defibrillation (AED) administration.Advanced Life Support paramedics are authorised to perform defibrillation, administer intravenous adrenaline and fluid, and insert a supraglottic airway.Intensive care ambulance paramedics are authorised to conduct additional treatments and interventions, such as endotracheal intubation (including rapid sequence intubation), as well as administer a wider range of intravenous medications.

Data source and definitions
For this study, we collected data from the VACAR.The registry was established in 1999, recording all OHCA cases attended by EMS in the state of Victoria.More than 150 data elements are collected by VACAR, including the Utstein-style descriptors 12 and patient discharge outcomes from hospital records for cases that are transported to hospitals. 13In this study, RVF refers to all initially shockable arrests who received three or more consecutive defibrillations, either from EMS or bystander, without achieving ROSC.Non-RVF refers to all other initially shockable arrests, including those with less than three consecutive defibrillations, either from EMS or bystander, or non-consecutive defibrillation attempts.EMSattempted resuscitation refers to any attempt at defibrillation or chest compressions by EMS. 12 Resuscitation time refers to the total time from the commencement of EMS CPR to the end of CPR either upon achieving ROSC or upon terminating resuscitation efforts.

Study outcomes
The primary outcome of this research was survival to hospital discharge.The secondary outcomes included the incidence of RVF and non-RVF and the number of patients who achieved ROSC and survived the event (pulse at hospital arrival).

Data analysis
Statistical analyses were performed using STATA statistical software 18 (StataCorp, 2015, College Station, TX).All hypothesis tests were two-sided and p-values of less than 0.05 were considered statistically significant.
Arrest characteristics and survival outcomes are reported using descriptive statistics stratified by RVF and non-RVF status.To measure differences in baseline characteristics and survival outcomes, the chi-square test and Mann-Whitney U test were used, as appropriate.Long-term trends in survival to hospital discharge for RVF and non-RVF patients were assessed using a non-parametric test for trend.
Annual crude incidence rates of RVF and non-RVF were calculated per 100,000 population.The estimated residential population was obtained from the Australian Bureau of Statistics (https://www.abs.gov.au).Trends in incidence were assessed for the RVF and non-RVF groups using a non-parametric test for trend. 14ultivariable logistic regression models were used to identify: 1) factors associated with the development of RVF; and, 2) the association between RVF and survival to hospital discharge.Models were adjusted for: age in years, male sex, comorbidities, the presence of bystander cardiopulmonary resuscitation (CPR), whether the event was witnessed, defibrillation by a bystander, arrest aetiology, public location, metropolitan region, and year of cardiac arrest.To account for resuscitation time bias in the survival to hospital discharge model, we also performed a sensitivity analysis which included the total resuscitation time.Results from these models were reported as adjusted odds ratios (OR) with 95% confidence intervals (CI).

Trends in incidence and survival
Trends in the proportion of RVF and non-RVF cases over the study period are presented in Fig. 2. The proportion of non-RVF cases increased from 52% in 2010 to 60% in 2019 (p-trend < 0.001).In contrast, the proportion of RVF cases decreased from 48% in 2010 to 40% in 2019 (p-trend < 0.001).Trends in incidence of RVF and non-RVF cases over the study period are shown in Fig. 3.The overall incidence of RVF cases decreased significantly from 7.7 cases per 100,000 population in 2010 to 5.6 cases per 100,000 population in 2019 (p-trend = 0.01).In comparison, there was no significant change in the incidence of non-RVF cases (ptrend = 0.37).
Fig. 4 shows the unadjusted trend in survival to hospital discharge in RVF and non-RVF patients over the study period.Survival to hospital discharge in the non-RVF cohort increased significantly from 41% in 2010 to 53% in 2019 (p-trend = 0.01).Similarly, the proportion of RVF patients who survived to hospital discharge increased significantly from 26% in 2010 to 31% in 2019 (p-trend = 0.004).To determine whether our results were influenced by resuscitation time, we repeated the above analysis by including resuscitation time in the model (Table 2).In this model, increasing resuscitation time was significantly associated with reduced odds of survival to hospital discharge (OR 0.983, 95% CI: 0.980, 0.985), and only modestly attenuated the impact of RVF on survival to hospital discharge (OR 0.585, 95% CI: 0.519, 0.659).

Discussion
Our analysis of EMS-attended OHCA over a 10-years period in Victoria, Australia suggests that the incidence of initially shockable arrests involving RVF is decreasing significantly year on year.Our results also suggest that RVF is associated with a 50% reduction in the odds of survival, even after adjusting for confounding factors, including resuscitation time.Importantly, the likelihood of survival to hospital discharge increased over time for both non-RVF and RVF cases.Our multivariable models suggest that EMS-witnessed arrests, initial defibrillation by a bystander and bystander CPR were associated with a lower likelihood of RVF and improved survival to hospital discharge.These findings suggest that the development of RVF may be mitigated by optimisations in the chain of survival and the delivery of early basic life support.
In this study, the long-term trend of RVF incidence reduced significantly over time from 7.7 to 5.6 cases per 100,000 population.A study conducted in Osaka prefecture in Japan between 1998 and 2006 which included 1733 patients with VF, reported different findings. 8  of survival.However, the definition of RVF differed from that used in our study.They defined RVF as VF/VT that persisted after hospital arrival and which was preceded by at least one EMS shock.This definition might have omitted patients who achieved ROSC after three or more shocks in the prehospital setting.This may partly explain their very low incidence of 0.5 cases per 100,000 population.It is not clear why the incidence of RVF reduced over time in our study.However, our results suggest that bystander interventions were associated with reduced odds of RVF, and bystander administration of CPR and defibrillation have increased over time in our region. 11Data from Victoria, Australia, showed that, for OHCA events witnessed by bystanders who received an attempted resuscitation by EMS, the rate of bystander CPR increased from 70% to 77% between 2011-2012 and 2020-2021 (p = 0.01). 11Further, initial defibrillation by paramedics reduced from 81% to 77% (p < 0.001), and this was met by close to a doubling in the use of AEDs by bystanders (7% to 13%, p = 0.002) over the same period. 11Efforts to promote bystander-administered CPR and prompt defibrillation may further reduce the incidence of RVF.
RVF was associated with decreased odds of survival in our study.The prognosis of RVF is poor in the published literature. 7,15However, a number of modifiable factors and interventions could be used to increase survival outcomes for RVF cases.The ARREST trial demonstrated that the use of extracorporeal membrane oxygenation (ECMO) was associated with improved outcomes compared to standard advanced care treatments (43% vs. 7%) in RVF patients. 9oreover, findings from the ALPS trial highlighted that early administration of amiodarone compared to a placebo significantly increased the likelihood of survival to hospital discharge (37.1% vs. 28.0%)and survival with good functional recovery (31.6% vs. 23.3%)for RVF patients. 16The DOSE-VF trial also showed that both vector change and the use of double sequential defibrillation in RVF patients improved survival compared to standard defibrillation attempts. 17Although many regions are yet to adopt these interventions for RVF patients, amiodarone is already administered for OHCA in our region, and our observations correlate with those from the ALPS trial. 18Also, a trial involving prehospital ECMO CPR is currently underway in Victoria, 19 contributing to the ongoing efforts to enhance the management and outcomes of RVF.
The definition used in our study reflects those used elsewhere, 6,7 and requires RVF patients to have three or more consecutive shocks which may be associated with longer resuscitation time.In our study, patients with RVF had a longer median resuscitation time compared to the non-RVF group.In OHCA, resuscitation time that exceeds 10 minutes is associated with poor outcomes, and survival is only 1% if resuscitation time exceeds 35 minutes. 20,21To account for resuscitation time bias, we performed a sensitivity analysis which included resuscitation time in the multivariable models.Although increasing resuscitation time was associated with reduced odds of survival, it only moderately attenuated the impact of RVF on survival.This finding suggests that the impact of RVF on survival is independent of resuscitation time.
Community programs targeting public awareness of the use of public access defibrillators and delivering high-quality CPR are needed.Future research should focus on exploring factors that influence the rate of successful defibrillation on RVF patients including the optimal amount of energy used, 22 pad position to lower transthoracic impedance, 23 the influence of patient's weight on shock success 22 and shock impedance. 24There is also value in examining RVF in greater detail.It is not clear how patient characteristics and outcomes change with an increasing number of consecutive shocks.To date, existing studies have explored the relationship between total shocks and outcome, 25,26 and it is not known how representative these populations are of RVF cases.

Limitations
Our study has several limitations.The study is retrospective in nature.The definition of RVF in our study may not be universally applicable, and it is possible that this definition included recurrent VF cases which could impact the accuracy of our findings.Additionally, approximately 2.5% of cases were missing RVF status and these  cases were excluded from the analysis.Finally, treatments provided in hospitals are not reported which may influence patient outcomes.

Conclusion
RVF accounts for 43% of initially shockable OHCA, although the incidence of RVF is declining.RVF is associated with a 50% reduction in the risk-adjusted odds of survival, however may be preventable with the early provision of bystander CPR and defibrillation.Community initiatives that focus on raising public awareness about the importance of administering CPR and the utilisation of publicly accessible defibrillators before EMS arrival are warranted.More research is also needed to examine the association between defibrillation characteristics and the likelihood of developing RVF.

Fig. 3 -
Fig. 3 -Crude incidence of RVF and non-RVF cases over the study period.

Fig. 4 -
Fig.4-Unadjusted trends in survival to hospital discharge for RVF and non-RVF cases over the study period.

Table 2
shows the association between RVF and survival to hospital discharge after adjustment for arrest factors.RVF was associated with a 50% reduction in the odds of survival to hospital discharge
They reported that the overall incidence of shockresistant VF remained stable, despite improvements in their chain